The present invention relates generally to the field of cosmetic compositions containing ascorbic acid and acetone in bioavailable form. In particular, this invention relates to a topically-applied composition incorporating a vitamin C derivative that is absorbed efficiently and that effectively establishes and maintains beneficial levels of ascorbic acid and acetone in the dermal layer of the skin.
Ascorbic acid, synonymously referred to herein as vitamin C, is essential in the human diet for the prevention of scurvy, a disease characterized by weakened connective tissue resulting from improper collagen production. The formation and maintenance of collagen, the fibrous constituent of bone, cartilage, and connective tissue, is a major function of vitamin C (Kivirikko, K. I., and R. Myllyla 1985 Ann. N.Y. Acad. Sci. 460: 187-201; Tajima, S., and S. R. Pinnell 1996. J. Dermatol. Sci. 11: 250-253). Human skin is particularly sensitive to the availability and action of ascorbic acid, as it is the largest organ in the body, and because the dermal layer of the skin is composed of approximately 70 to 80% collagen by dry weight. By stimulating and regulating the synthesis of collagen, vitamin C increases the elasticity and structural integrity of human skin and inhibits the formation of wrinkles. U.S. Pat. No. 4,983,382 suggests that supplementing dermal tissue with ascorbic acid delivered percutaneously through the stratum corneum can result in improved tone and luster, decrease in fine lines and wrinkles, and improved elasticity.
Another important benefit of ascorbic acid is its protective effect against oxidative damage to the skin. A major cause of cutaneous damage is the generation of reactive oxygen species by chemical pollutants, smoking, and particularly ultraviolet (UV) radiation. Reactive oxygen species can damage lipids, proteins, and nucleic acids in skin cells, which in turn can lead to the development of cutaneous cancer and photoaging (Fisher, G. J., Z. Q. Wang, S. C. Datta, J. Varani, S. Kang, and J. J. Voorhees 1997. N. Engl. J. Med. 337: 1419-1429). Ascorbic acid is a critical component of the nonenzymatic antioxidant defense system in the skin. At higher concentrations, ascorbic acid is known to neutralize singlet oxygen, superoxide anions, and hydroxy radicals in the skin before they can cause damage (Buettner, G. R., and B. A. Jurkiewicz. 1996. In: Cadenas, E., Packer, L., eds. Handbook of antioxidants. pp. 91-115).
Numerous investigators have reported that high levels of ascorbic acid in the skin, produced by topical application of the vitamin, provides some degree of protection against UV radiation, particularly UVA (Darr, D., S Dunston, H. Faust, and S. Pinnell. 1996. Acta Derm. Venereol. (Stockh). 76: 264-268; Black, H. S., and J. T. Chan. 1975. J. Invest. Dermatol. 65: 412-414). This protective effect is apparently due to the scavenging of oxygen free radicals generated in the cytosol by UVA rays. The concentration of ascorbic acid in the skin cell is inversely related to the level of oxygen free radical activity and thus the degree of cellular damage (Darr, D., S. Combs, S. Dunston, T. Manning, and S. Pinnell. 1992. Brit. J. Dermatol. 127: 247-253). Ascorbic acid also has a protective effect against cutaneous damage caused by UVB irradiation. When vitamin C was applied topically to pig and human skin prior to UVB irradiation, erythema and sunburn were prevented (Darr, D., S. Combs, S. Dunston, T. Manning, and S. Pinnell 1992. Brit. J. Dermatol. 127: 247-253; Murray, J., D. Darr, J. Reich, and S. Pinnell 1991. J. Invest. Dermatol. 96: 587). Photoaging changes in the skin of humans and of hairless mice were decreased after topical application of ascorbic acid (Traikovich, S. S. 1999. Arch. Otolaryngol. Head Neck Surg. 125: 1091-1098; Bissett, D. L., R. Chatterjee, and D. P. Hannon. 1990. Photoimmunol. Photomed. 7: 56-62).
Topical application of ascorbic acid has been shown to inhibit the release of histamine from cellular membranes, thus preventing allergic reactions among individuals with sensitive skin. Topical ascorbic acid was demonstrated to protect against UV-induced immunosuppression and tolerance to contact antigen in mice (Nakamura, T., S. R. Pinnell, D. Darr, et al. 1997. J. Invest. Dermatol. 109: 20-24). Finally, there is evidence that vitamin C can minimize age-related skin discoloration by inhibiting tyrosinase and the formation of melanin (Tomita, Y., A. Hariu, C. Mizumo, and M. Seyi. 1980. J. Invest. Dermatol. 75(5): 379-382; Maeda, K., and F. M. Arbutin 1996. J. Pharmacol. Exp. Ther. 276: 765-769).
All of the aforementioned beneficial effects of ascorbic acid, particularly those resulting from the antioxidant activity of this substance, will be optimized only if high levels of vitamin C are established and maintained in the tissues Uacques, P. F., and L. T. Chylack. 1991. Am. J. Clin. Nutr. 53: 352S-355S). Attempts to increase skin levels of ascorbic acid through increased ingestion have been futile because vitamin C concentration of the skin is regulated, and limited, by active transport mechanisms (Rumsey, S. C., and M. Levine. 1998. J. Nutr. Biochem. 9: 116-130). Alternatively, the direct delivery of a high concentration of ascorbic acid through the stratum corneum barrier into the skin will effectively increase the pool of protective antioxidants and enhance collagen synthesis. However, there are many obstacles that must be overcome to reach this goal. For example, as a water-soluble molecule, vitamin C is not stored well in the tissues and is rapidly removed from the body, with a half-life of about 20 days in the human (Ritchey, S. J. 1965. Am. J. Clin. Nutr. 17: 57-114). Also, because of its hydrophilic nature, vitamin C is not absorbed well into specific tissues, especially the skin, which naturally repels water and water-soluble substances. Depending on the vehicle used, only about 8% of topically-applied ascorbic acid is actually absorbed into the skin (Darr, D., S. Combs, S. Dunston, T. Manning, and S. Pinnell. 1991. J. Invest. Dermatol. 96: 590). In addition, ascorbic acid is very unstable in aqueous solutions at neutral pH (Meucci et al. 1985. Acta. Vitaminol. Enzymol. 7(3-4): 147-154). Taken together, the lack of stability and poor cutaneous absorption of ascorbic acid limit the effectiveness of most topical vitamin C preparations.
Numerous attempts have been made to overcome the aforementioned difficulties in order to deliver effective concentrations of ascorbic acid directly to the dermal layer of the skin. For example, the hydroxyl groups at carbon 2 and at carbon 3 have been esterified to phosphate groups to form ascorbyl-2-phosphate and ascorbyl-3-phosphate, respectively. These ascorbate derivatives are remarkably stable in aqueous solutions, but because of the negative charge of the phosphate groups, they do not traverse the stratum corneum. Topical application of a serum that contained 13 wt % of magnesium ascorbyl 2-phosphate failed to increase skin levels of ascorbic acid (Pinnell, S. R., H. Yang, M. Omar, et al. 2001. Dermatologic Surgery 27 (2): 137-142), verifying previous studies that had documented the marginal percutaneous absorption of this ascorbate derivative (Kobayashi, S., M. Takehana, S. Itoh, and E. Ogata. 1996. Photochemistry and Photobiology 64(1): 224-228).
In order to increase percutaneous absorption, ascorbate derivatives possessing a lipophilic moiety have been synthesized. U.S. Pat. No. 5,409,693 discloses topical application of lipophilic fatty acid esters of ascorbic acid to facilitate percutaneous absorption in the treatment of sunburn. Ascorbyl-6-palmitate, in which palmitic acid is esterified to the hydroxyl group at carbon 6 of ascorbic acid, is the fatty acid ester that is most widely used in topical vitamin C preparations. However, previous studies of ascorbyl-6-palmitate failed to demonstrate protection against photoaging in mouse skin (Bissett, D. L., R. Chatterjee, and D. P. Hannon. 1990. Photodermatol Photoimmunol Photomed 7: 56-62), and a recent study demonstrated that topical application of a serum containing 10 wt % of ascorby-6-palmitate resulted in no significant increase in skin levels of ascorbic acid (Pinnell, S. R., H. Yang, M. Omar, et al. 2001. Dermatologic Surgery. 27(2): 137-142).
Topical application of ascorbic acid in its unmodified form has been the most effective means of delivering vitamin C to the dermal layer of the skin (see U.S. Pat. No. 4,983,382; 5,140,043; 6,299,889). However, the results of recent studies indicate that ascorbic acid must be formulated at pH levels of less than 3.5 to enter the skin, and that the maximal concentration for optimal percutaneous absorption is 20 wt % (Pinnell, S. R., H. Yang, M. Omar, et al. 2001. Dermatologic Surgery. 27(2): 137-142). At this concentration and pH, ascorbic acid is known to disrupt the epidermis and irritate the skin such that most beneficial effects may be negated. In consideration of consumer acceptance, most commercial ascorbic acid formulations contain much less than 20 wt % of the vitamin and are maintained at a more neutral pH. Under these conditions, the absorption and effectiveness of ascorbic acid are limited.
Acetone in low concentrations is known to have beneficial effects in the skin. Acetone has been shown to have anti-inflammatory effects in cases of contact dermatitis (Sjogren, F., O. Groth, and C. Anderson. 1999. Contact Dermatitis. 41(1): 22-29). In inflamed skin treated with acetone, erythema and edema were diminished and there was observed a significant decrease in the presence of mononuclear cells, an indicator of inflammation. The reason for this is unclear, but it may be due to an alteration of intercellular lipid organization and cellular membrane lipid organization, thus influencing membrane receptor function. Despite its benefits, acetone applied directly to the skin in high concentrations can disrupt the structural integrity of the epidermis and cause dryness, resulting in skin irritation.
The object of the present invention is to provide a method of establishing and maintaining levels of ascorbic acid and acetone in the dermal layer of the skin sufficient to produce beneficial effects.
Ascorbic acid prevents oxidative damage and promotes collagen synthesis in the skin, and acetone has anti-inflammatory effects in the skin. However, topically-applied ascorbic acid is not well-absorbed, and direct application of acetone can disrupt the structural integrity of the skin.
The present invention overcomes the aforementioned problems by providing a composition for topical application that incorporates 5,6-O-isopropylidene L-ascorbic acid, a derivative of ascorbic acid that is more lipid soluble that ascorbic acid and thus better absorbed into the dermis with minimal disruption of the structural integrity of the skin. In the dermal layer of the skin, non-specific esterases hydrolyze 5,6-O-isopropylidene L-ascorbic acid to form ascorbic acid and acetone.
Another object of the present invention is to provide a stable, cosmetically-acceptable carrier in which 5,6-O-isopropylidene L-ascorbic acid can be applied topically.